Pd-catalyzed arylation of silyl enol ethers of substituted α-fluoroketones

Article abstract of DOI:10.1039/b900311h

α-Fluoro-α-aryl-ketones were synthesized by the Pd-catalyzed cross-coupling of aryl bromides with either α-fluoroketones or their corresponding silyl enol ethers. The direct arylation with an α-fluoroketone requires a strong base, such as potassium tert-b

Full text of DOI:10.1039/b900311h

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Pd-catalyzed arylation of silyl enol ethers of substituted a-fluoroketones†
Yong Guo, Brendan Twamley and Jean’ne M. Shreeve*
Received 8th January 2009, Accepted 11th February 2009
First published as an Advance Article on the web 13th March 2009
DOI: 10.1039/b900311h
a-Fluoro-a-aryl-ketones were synthesized by the Pd-catalyzed cross-coupling of aryl bromides with
either a-fluoroketones or their corresponding silyl enol ethers. The direct arylation with an
a-fluoroketone requires a strong base, such as potassium tert-butoxide, and under these conditions the
presence of a base-sensitive functional group is not compatible. However, good functional tolerance
was achieved when the anionic coupling moieties were generated from the silyl enol ethers obtained by
reacting a-fluoroketones with tetrabutylammonium (tripheny1silyl)difluorosilicate (TBAT) as the
fluoride source under nearly neutral conditions. The aryl halides with a carbmethoxy, nitro, cyano or
carbonyl group were used. The reaction with nonfluorinated silyl enol ether 1h gave a cross-coupling
product in low yield.
Introduction
Fluoroorganic chemistry provides surprising and intellectual
stimulation in theoretical, synthetic, and biomedical chemistry,
and materials science.1 Tertiary a-fluorinated ketones have re-
ceived much attention recently because compounds having an
a-fluorocarbonyl moiety exhibit interesting biological activity,
such as effective mimics of a-hydroxy ketones, useful probes for
various biological processes, and enzyme inhibitors.2 Electrophilic
Scheme 1 The reaction of fluorinated silyl enol ether with 1-bromo-
fluorination of a ketone3 and functionalization of a fluorinated
4-nitrobenzene.
building block4 give rise to two main strategies for the prepa-
ration of tertiary a-fluorinated ketones as well as a few other
systems.5 However, limited reports of methods to prepare a-aryl-
In order to expand the utilization of both silyl enol ethers
and functionalized halides, the reaction conditions of silyl enol
a-fluorocarbonyl compounds,5d especially synthetic routes to a-
aryl-a-fluoroketones, are available. Reactivities of fluorinated sub-
ether 1b with halides was screened. Selected conditions were
depicted in Table 1. Initially the Pd-Bu3SnF system7 was used
strates were often found to be different and sometimes unexpected
compared to their nonfluorinated analogues.6 Thus, although we
developed an approach to a,a-difluoroketones from difluoroenol
silyl ethers,7 it was still interesting to observe the arylation of the
substituted a-monofluoroketones even though there have been
a few reports of coupling reactions of nonfluorinated enol silyl
ethers.8
(Entry 6). However, only a small amount of 3b was obtained.
Therefore, several other fluorides were tried. The arylation of
enol silyl a-monofluoroketone 1b was catalyzed by 3.75 mol%
bis(dibenzylideneacetone)palladium (Pd(dba)2) and 7.5 mol%
t-Bu3P in the presence of tetrabutylammonium (triphenylsi-
lyl)difluorosilicate (TBAT) in toluene at elevated temperature. A
moderate yield of 3b resulted (Table 1, Entry 1). The ketone which
results from the hydrolysis of silyl enol ether 1a was formed as the
major side product. Several reactions were carried out in order
to determine how to reduce its formation. The yield was slightly
improved when the aryl iodide was used instead of bromide since
the iodide is more reactive (Entry 2); however, slightly larger
amounts of hydrolysis products were found. With increase in
concentration of the palladium catalyst and phosphine, the yield
of aryl product was increased, and the hydrolysis reaction was
reduced. Tetrabutylammonium difluorophenylstannate, a fluoride
source similar to TBAT, showed poor results (Entry 5). In all cases,
we found the biaryl in a low yield.9
Result and discussion
Palladium-catalyzed cross-coupling reactions of a-aryl-b,b-
difluoroenol silyl ethers with aryl bromides proceed smoothly
with good functional compatibility in the presence of tri-tert-
butylphosphine and tri-n-butyltin fluoride using palladium ac-
etate as catalyst.7 However, the yield decreased dramatically
when a-phenyl-b-fluoroenol silyl ether 1 reacted with 1-bromo-
4-nitrobenzene under similar conditions (Scheme 1).
The time at which the silyl enol ether was introduced into the
reaction mixture after reaction initiation appears to be important
in some cases. For example, with bromobenzene the results were
independent of the time of addition of silyl enol ether (Table 2).
However, for reasons which are not entirely clear, the yield
of 3 was reduced when addition of the silyl enol ether to a
Department of Chemistry, University of Idaho, Moscow, Idaho 83844-2343,
USA. E-mail: jshreeve@uidaho.edu
† Electronic supplementary information (ESI) available: All spectroscopic
data of new compounds and single-crystal X-ray diffraction analyses of
compound 3e. CCDC reference number 715296. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/b900311h
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Table 1 Screen of conditions of silyl enol ether 1b with halides
Table 2 Influence of preheating timea
Mol%
Mol%
% Yield of
% Yield 3b % Yield 4a biaryl
Entry Halide Pd(dba)2 t-Bu3P
Preheating
time (min)
Entry
Halide
3 : 4a
% Yield of biaryl
1
2
3
2b
2h
2b
2b
2b
2b
3.75
3.75
7.5
15
3.75
3.75
7.5
7.5
15
30
7.5
7.5
44
45
60
73
28
25
41
50
26
13
65
52
7
9
9
12
12
2
1
2
3
4
5
2a
2a
2f
2f
2f
0
2
0
2
3
(3a : 4a) 64 : 36
(3a : 4a) 61 : 39
(3f : 4a) 69 : 31
(3f : 4a) 57 : 43
(3f : 4a) 41 : 59
n.d.b
n.d.
14
17
14
4
5b
6c,d
a Conditions: in toluene (0.7 mL), at 90 ◦C for 20 min, silyl enol ether
of ketone (0.33 mmol), aryl halides (0.66 mmol), TBAT (0.40 mmol).
a Conditions: in toluene (0.7 mL), at 90 ◦C for 20 min, silyl enol ether 1a
(0.33 mmol), aryl halides (0.66 mmol), TBAT (0.40 mmol), and Pd(dba)2
(0.05 mmol, 15 mol%), t-Bu3P (30 mol%). b n.d. – not determined.
b Tetrabutylammonium
difluorophenylstannate
[Bu4N][Ph3SnF2 ]
(0.40 mmol) instead of TBAT. c 3 eq n-Bu3SnF was used instead of TBAT.
d Reaction time was 10 hours.
A remarkable feature of the reaction is the good tolerance
to electron-withdrawing base-sensitive functional groups, e.g.,
carbmethoxy, nitro, cyano or carbonyl group. Single-crystal X-
ray diffraction of 3e confirmed the structure (Fig. 1; CCDC
715296). The 4-nitrophenyl group is introduced at the same carbon
with fluorine. When non-fluorinated 1h was used, the cross-
coupling product 3m was formed in a 15% yield. In Scheme 2,
an equal number of equivalents of 1a and 1h were used. The
unusual fact that compound 1h (with less steric hindrance) gave a
reaction mixture which contained halide 2f was further (0 min
vs 2, 3 min) into the heating cycle. Interestingly, the extent
of self-coupling of the halide did not change (Table 2, Entries
3 to 5).
After the optimization of reaction conditions, various silyl enol
ethers and halides were studied (Table 3). Unlike the reactions
of difluoro7 or nonfluorinated enol silyl ethers,8 this route avoids
using toxic tri-n-butyltin fluoride, which makes the reaction more
environmentally friendly. It was found that an excess of aryl halide
was necessary to ensure arylation; hydrolysis of the silyl enol
ether gave rise to the main side product and biaryls were also
formed. Several silyl enol ethers were tested. Triethylsilyl (TES)
and trimethylsilyl (TMS) reagents gave similar results (Entry 7).
In most cases, TES-substituted silyl enol ethers were used because
of the ease of separation of reaction mixtures and of the lower
decomposition when subjected to column chromatography on
silica gel. The reaction rate of 1d (seven-membered ring) was
observed to be slower than that of 1a (six-membered ring), thus
the reaction was carried out with more TBAT for a prolonged
period of time. The reactions of cyclic silyl enol ethers apparently
proceeded more efficiently than that of acyclic ethers such as 1f.
The (E)-structure of silyl enol ether of 1f was confirmed by the
NOE effect.10
The product was an a,a-difluoroketone 5 when difluoroenol
silyl ether 1g was used. The current reaction conditions are not
suited for further coupling of 5. We have reported cross-coupling
reactions of 5 with many aryl halides.7 The reaction mechanism
may differ for each.
Fig. 1 Single-crystal X-ray structure of 3e.
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Table 3 Arylation of enol silyl ethers of substituted a-monofluoroketones
Entry
1
Silyl enol other
Aryl bromide
Product
% Yielda
64
2
3
4
1a
1a
1a
73
67
61
5
1a
1a
61
6
7
8
61
66
62
2b
9
10
11
2d
2e
2e
55b
57b
65
1d
12
2b
25
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Table 3 (Contd.)
Entry
13
Silyl enol other
Aryl bromide
Product
% Yielda
90
2b
14
2e
15c
a Conditions: in toluene (0.7 mL), at 90 ◦C for 20 min, silyl enol ether of ketones (0.33 mmol), aryl halides (0.66 mmol), TBAT (0.40 mmol), and Pd(dba)2
(0.05 mmol, 15 mol%), t-Bu3P (30 mol%). b Run with TBAT (0.66 mmol) for 2 h. c The yield was determined by 1H NMR.
Table 4 Arylation of cyclic monofluoroketones
% Conversion
Entry Ketone Aryl halide Product of ketone
% Yield of 3a
Scheme 2 Comparison of reactivity of non-fluorinated and fluorinated
silyl enol ketones.
1
2
3
4
5
6
7
8
9
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
2a
2b
2i
2g
2g
2c
2d
2f
3a
3b
3n
3g
3g
3c
3d
3f
100
100
100
75
100
80
74
57
100
100
73b
72b
67b
84b
85c
11c
11c
4c
smaller quantity of the coupling product may be explained by the
ease of hydrolysis of 1h. The introduction of fluoride seemed to
stabilize the enolate, thus markedly reducing the generation of the
hydrolysis product compared to the non-fluorinated compound.
As a result, additional amounts of the coupling product were
formed.
2b
2g
3h
3o
70b
65c
10
a Yield based on converted ketone. b Conditions: in toluene (0.5 mL), at
90 ◦C for 1 h, ketone (0.33 mmol), aryl halides (0.36 mmol), t-BuOK
(0.36 mmol), and Pd(OAc)2 (0.0165 mmol, 5 mol%), t-Bu3P (5 mol%).
c Aryl halides (0.45 mmol).
For the first time an extensive method has been developed
for the synthesis of aryl-substituted tertiary a-fluoroketones by
Pd-catalyzed cross-coupling reactions. Traditionally, tertiary
a-fluoroketones were synthesized by electrophilic fluorination.3
However, most electrophilic reagents tend to be expensive and/or
difficult to prepare, and often the functional groups of the
reactants are incompatible withthe electrophiles. We are aware that
the enantioselective Pd-catalyzed allylation reaction of fluorinated
silyl enol ethers4 in a previous example avoided electrophilic
fluorination in the final step in the synthesis of tertiary
a-fluoroketones. However, the advantage of mild conditions and
good functional tolerance can not be fully embodied when
the substrates were limited to allyl ethyl carbonate and its
analogues. Thus, the discovery that a variety of aryl halides with
diverse functional groups are compatible in Pd-catalyzed cross-
coupling reactions of fluorinated silyl enol ethers has expanded
the scope of substrates. At the same time, this methodology
will be useful for the enantioselective synthesis of a-aryl
a-fluoroketones. The reduction of reactivity from cyclic fluori-
nated silyl enol ethers to acyclic moieties is common in arylation
and allylation.4
conditions that would lead to cross-coupling while concomitantly
preventing the formation of the two side products was key
to the reaction. It is very important to control the relative
speed of the generation of enolate anion and the insertion of
palladium into the halide in order to achieve the maximum amount
of desired cross-coupling product, e.g., a-aryl-a-fluoroketones.
The Pd(dba)2/t-Bu3P/TBAT system gave moderate yields of the
products. The nearly neutral reaction conditions not only increases
the functionality application, but also provides the possibility of
chiral synthesis.
Starting from ketones rather than via a silyl enol ether, it is also
possible to synthesize a-aryl-a-fluoroketones. The results appear
in Table 4. The reaction was catalyzed by palladium acetate and
tri-tert-butyl phosphine in the presence of potassium tert-butoxide.
With 1.1 equivalents of monobromobenzene, 4-bromotoluene, or
4-methoxyl-1-bromobenzene, the ketone (4a or 4b) was converted
completely (Entries 1, 2, 3 and 9). In order to realize full conversion
of the ketone, 1.5 equivalent of 4-bromobenzotrifluoride was
Since the silyl enolates tended to hydrolyze to generate ketones,
and aryl halides tended to generate biaryls, finding favourable
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Table 5 Arylation with an acyclic a-fluoroketone
enol ether 1a (92 mg, 0.33 mmol) was added via syringe with
stirring. After 20 minutes, the mixture was cooled and passed
through a short pad of silica gel. The precipitate was washed with
ethyl acetate. The solvent was removed under reduced pressure.
The desired product 3e (57 mg, 61%) was isolated by flash
chromatography using 10% ethyl acetate/hexane.
Entry
R
% Conversion of 4
% Yield of 3
1
2
3
H (4h)
CH3 (4f)
F (4g)
90
67
50
17
24
0
1
2-Fluoro-2-phenyl-1-tetralone (3a). IR (film): 1699 cm-1; H
NMR d 2.70–2.85 (m, 3H), 3.08–3.14 (m, 1H), 7.24 (d, J = 7.6 Hz,
1H), 7.32–7.38 (m, 5H), 7.39 (t, J = 7.6 Hz, 1H), 7.53 (td, J = 7.6,
1.2 Hz, 1H), 8.18 (dd, J = 7.6, 1.2, 1H). 19F NMR d -145.6 (t, J =
11.3 Hz). EI-MS (m/z, relative intensity): 240 (M+, 29), 118 (100),
90 (45). Anal. Calcd for C16H13FO (FW 240.3): C, 79.98; H, 5.45.
Found: C, 80.00; H, 5.40.
required (Entry 4 vs Entry 5). However, the conversion and yield
were poor even with excess of halide in entries 6 to 8, due to
the base-sensitive functional group. It was necessary to employ
nearly neutral conditions for those compounds, and using the
silyl enol ether was an effective way of doing this, as described
above.
Table 5 shows the limitation of the reaction. When using
the open-chain monofluoroketone (4h or 4f), 3 was obtained in
low yield. There are a number of mysterious features of these
reactions. For example, we currently have no good explanation for
the difference in levels of yield and conversion observed for the
reactions of 4a and 4h under identical reaction conditions. Like its
enolate from silyl enol ether (Entry 12, Table 3), ketone 4f gave a
poor yield of coupling product (Entry 2, Table 5). Arylation of the
difluoroketone did not occur, and as a result none of the coupling
product was obtained.
2-Fluoro-2-(4-methylphenyl)-1-tetralone
(3b). IR
(film):
1699 cm-1; 1H NMR d 2.33 (s, 3H), 2.63–2.87 (m, 3H), 3.05–3.13
(m, 1H), 7.14–7.26 (4H), 7.21 (d, J = 7.5 Hz, 1H), 7.38 (t, J =
7.5 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 8.16 (d, J = 7.5 Hz, 1H); 19
F
NMR d -142.7 (t, J = 9.9 Hz). EI-MS (m/z, relative intensity):
254 (M+, 15), 118 (100), 90 (36). Anal. Calcd for C17H15FO (FW
254.3): C, 80.29; H, 5.95. Found: C, 80.09; H, 5.85.
Ethyl 3-(1,2,3,4-tetrahydro-2-fluoro-1-oxo-2-naphthalenyl)benz-
onate (3c). IR (film): 1721, 1699 cm-1; 1H NMR d 2.68–2.89 (m,
3H), 3.19 (dt, J = 16, 4.5, 3H), 3.90 (s, 3H), 7.26 (d, J = 7.7 Hz,
1H), 7.40–7.46 (m, 2H), 7.51–7.55 (m, 2H), 8.04 (d, J = 7.7 Hz,
1H), 8.09 (s, 1H), 8.17 (d, J = 7.7 Hz, 1H); 19F NMR d: -147.8
(dd, J = 17, 11 Hz). EI-MS (m/z, relative intensity): 283 (M+-Me,
0.68), 86 (16), 41 (100). Anal. Calcd for C18H15FO3 (FW 298.3): C,
72.47; H, 5.07. Found: C, 72.20; H, 5.17.
In summary, the synthesis of tertiary a-fluoroketones by
palladium-catalyzed arylation was successful. By using silyl enol
ethers, a wide range of halides with good functionality toler-
ance can be utilized. With base-insensitive halides, fluoroketones
rather than silyl enol ethers can be used directly to achieve
coupling.
4-(1,2,3,4-Tetrahydro-2-fluoro-1-oxo-2-naphthalenyl)benzonit-
rile (3d). IR (film): 2230, 1695, 1602, 1233 cm-1; 1H NMR d 2.58–
2.76 (m, 2H), 2.81–2.93 (m, 1H), 3.26 (dt, J = 17.5, 6.0 Hz, 1H),
7.30 (d, J = 7.7 Hz, 1H), 7.39–7.81 (m, 6H), 8.15 (d, J = 7.7 Hz,
1H). 19F NMR d -153.0 (dd, J = 19.7, 11.3 Hz). EI-MS (m/z,
relative intensity): 265 (M+, 20), 118 (100), 90 (44).Anal. Calcd
for C17H12FNO (FW 265.3): C, 76.97; H, 4.56, N,5.28. Found: C,
77.20; H, 4.47, N, 5.46.
Experimental section
General methods
Silyl enol ethers4a were prepared by literature methods.
Selectfluorꢀ was used as fluoride source for the preparation
R
of fluorinated silyl enol ethers. TBAT was synthesized from
Ph3SiF and tetrabutylammonium and difluorophenylstannate was
prepared from Ph3SnF.11,12 A 1M toluene solution of P(t-Bu)3
was purchased from Aldrich Chemical Co. and used as received
or was made by diluting pure tri-tert-butylphosphine from Alfa
Aesar with dry toluene. Toluene was distilled under nitrogen
over sodium prior to use. All other chemicals were used as
received from commercial sources. 1H and 19F NMR spectra
were obtained on a 300- or 500-MHz spectrometer, and chemical
shifts were recorded relative to tetramethylsilane, and CFCl3,
respectively. The solvent was CDCl3 unless otherwise stated. The
purity of products was determined by C, H, and N elemental
analyses.
2-Fluoro-2-(4-nitrophenyl)-1-tetralone (3e). IR (film): 1698,
1
1603, 1522, 1349 cm-1; H NMR d 2.65–2.76 (m, 2H), 2.84–2.94
(m, 1H), 3.29 (dt, J = 17.1, 5.5 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H),
7.42 (t, J = 7.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.59 (td, J = 7.6,
1.3 Hz, 1H), 8.14 (dd, J = 7.6, 1.3 Hz, 1H), 8.23 (d, J = 8.4 Hz,
2H); 19F NMR d -153.5 (dd, J = 19.7, 11,3 Hz). EI-MS (m/z,
relative intensity): 285 (M+, 31), 118 (100), 90 (48). Anal. Calcd
for C16H12FNO3 (FW 285.3): C, 67.36; H, 4.24; N, 4.91. Found:
C, 67.47; H, 4.23, N, 5.24.
2-Fluoro-2-(4-acetylphenyl)-1-tetralone (3f). IR (film): IR
1
(film): 1679 cm-1; H NMR d 2.59 (s, 3H), 2.65–2.91 (m, 3H),
3.20 (dt, J = 16.1, 5.0 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.41
(t, J = 7.6 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.57 (td, J =
7.6, 1.2 Hz, 1H), 7.95 (d, J = 8.2 Hz, 2H), 8.17 (dd, J = 7.6,
1.2 Hz, 1H); 19F NMR d -151.4 (t, J = 14.1 Hz). EI-MS (m/z,
relative intensity): 282 (M+, 23), 118 (100), 90 (43). Anal. Calcd
for C18H15FO2 (FW 282.3): C, 76.58; H, 5.36. Found: C, 76.45; H,
5.43.
General procedure for the arylation of silyl enol ether
To a mixture of Pd(dba)2 (28 mg, 0.05 mmol), TBAT (210 mg,
0.40 mmol) and aryl halide 2e (133mg, 0.66 mmol), was added
freshly dried toluene (0.7 mL) and t-Bu3P (0.1 mL of 1 M toluene
◦
solution, 0.1 mmol) at 90 C under a nitrogen atmosphere. Silyl
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2-Fluoro-2-(4-trifluoromethylphenyl)-1-tetralone
(3g). IR
pressure. The desired product 3a (58 mg, 73%) was isolated by flash
(film): 1699, 1333, 1125 cm-1; 1H NMR d 2.67–2.92 (m, 3H), 3.23
(dt, J = 16.7, 5.1 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.39–7.65 (m,
6H), 8.17 (d, J = 7.7 Hz, 1H); 19F NMR d -63.2 (s, 3F), -151.8 (t,
J = 14.1 Hz, 1F); EI-MS (m/z, relative intensity): 308 (M+ - HF,
23), 118 (100), 90 (44). Anal. Calcd for C17H12F4O (FW 328.3): C,
66.23; H, 3.92. Found: C, 66.10; H, 3.88.
chromatography using 5% ethyl acetate/hexane.
2-Fluoro-2-(4-methoxyphenyl)-1-tetralone (3n). IR (film):
1
1697 cm-1; H NMR d 2.65–2.90 (m, 3H), 3.04–3.12 (m, 1H),
3.79 (s, 3H), 6.87 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 7.6 Hz, 1H),
7.29–7.41 (m, 3H), 7.52 (td, J = 7.6, 1.3 Hz, 1H), 8.17 (dd, J =
7.6, 1.3 Hz, 1H); 19F NMR d -140.7 (t, J = 8.5 Hz, 1H). EI-MS
(m/z, relative intensity): 250 (M+ - HF, 100), 235 (18), 207 (25),
178 (39). Anal. Calcd for C17H15FO2 (FW 270.3): C, 75.54; H,
5.59. Found: C, 75.19; H, 5.51.
2-Fluoro-2-(4-methylphenyl)-6-methoxy-1-tetralone (3h). IR
(film): 1690, 1599, 1256 cm-1; 1H NMR d 2.35 (s, 3H), 2.65–2.85
(m, 3H), 2.95–3.15 (m, 1H), 3.88 (s, 3H), 6.68 (d, J = 2.3 Hz,
1H), 6.92 (dd, J = 8.8, 2.3 Hz, 1H), 7.16–7.28 (4H), 8.17 (d, J =
8.8 Hz, 1H); 19F NMR d -143.2 (t, J = 9.9 Hz). EI-MS (m/z,
relative intensity): 284 (M+, 13), 264 (37), 221 (13), 148 (100), 120
(18). Anal. Calcd for C18H17FO2 (FW 284.3): C, 76.04; H, 6.03.
Found: C, 76.50; H, 6.03.
2-Fluoro-2-(4-trifluoromethylphenyl)-6-methoxy-1-tetralone
(3o). IR (film): 1680, 1599 cm-1; 1H NMR d 2.63–2.86 (m, 3H),
3.10–3.25 (m, 1H), 3.88 (s, 3H), 6.72 (d, J = 2.2 Hz, 1H), 6.93 (dd,
J = 8.8, 2.2 Hz, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.2 Hz,
2H), 8.14 (d, J = 8.8 Hz, 1H); 19F NMR d -62.1 (s, 3F), -150.5 (t,
J = 13.8 Hz, 1F). EI-MS (m/z, relative intensity): 338 (M+, 25),
319 (3.46), 148 (100), 120 (28). Anal. Calcd for C18H14F4O2 (FW
338.3): C, 63.91; H, 4.17. Found: C, 64.15; H, 4.11.
4-(6-Fluoro-6,7,8,9-tetrahydro-5-oxo-5H-benzocycloheptenyl)-
1
benzonitrile (3i). IR (film): 2230, 1699 cm-1; H NMR d 1.92–
2.06 (m, 1H), 2.21–2.60 (m, 3H), 2.96–3.06 (m, 1H), 3.23–3.33 (m,
1H), 7.26–7.32 (m, 2H), 7.38–7.48 (m, 2H), 7.58 (d, J = 8.6 Hz,
2H), 7.69 (d, J = 8.6 Hz, 2H). 19F NMR d -153.9 (dd, J = 38.7,
17.8 Hz). EI-MS (m/z, relative intensity): 279 (M+, 17), 251 (10),
160 (100), 129 (50), 104 (53), 91 (51), 77 (33). Anal. Calcd for
C18H14FNO (FW 279.3): C, 77.40; H, 5.05; N, 5.01. Found: C,
77.23; H, 5.09; N, 5.40.
Acknowledgements
We gratefully acknowledge the support of DTRA (HDTRA 1-07-
1-0024), NSF (CHE0315275), and ONR (N00014-06-1-1032).
2-Fluoro-2-(4-nitrophenyl)- 2-fluoro-2-(4-nitrophenyl)-1-benzo-
suberone (3j). IR (film): 1699, 1522, 1348 cm-1; 1H NMR d 1.93–
2.08 (m, 1H), 2.33–2.63 (m, 3H), 2.99–3.07 (m, 1H), 3.25--3.34 (m,
1H), 7.26–7.33 (m, 2H), 7.39–7.49 (m, 2H), 7.65 (d, J = 9.0 Hz,
2H), 8.25 (d, J = 9.0 Hz, 2H). 19F NMR d -153.4 (dd, J = 39.3,
17.9 Hz). EI-MS (m/z, relative intensity): 229 (M+, 20), 281 (45),
225 (18), 207 (55), 91 (42), 73 (100). Anal. Calcd for C17H14FNO3
(FW 299.3): C, 68.22; H, 4.71; N, 4.68. Found: C, 68.19; H, 4.74;
N, 5.23.
References
1 (a) P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis, Reactivity,
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6-Fluoro-6-(4-nitrophenyl)-4,4-dimethylcyclohex-2-enone (3k).
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T. Toru and M. Shiro, Angew. Chem. Int. Ed., 2008, 47, 4157; (b) J.-A.
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1
IR (film): 1690, 1604, 1522, 1348 cm-1; H NMR d 1.15 (s, 3H),
1.39 (s, 3H), 2.27–2.45 (m, 2H), 6.15 (d, J = 10.3 Hz, 1H), 6.90
(d, J = 10.3, 1.5 Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H), 8.24 (d, J =
8.5 Hz, 2H). 19F NMR d -150.5 (J = 37.4, 16.4 Hz). Anal. Calcd
for C14H14FNO3 (FW 263.3): C, 63.87; H, 5.39; N, 5.32. Found:
C, 63.92; H, 5.34; N, 5.31.
2-Fluoro-2-(4-methylphenyl)-1-phenyl-1-propanone
(3l). IR
(film): 1687 cm-1; H NMR d 1.90 (d, J = 23.1 Hz, 3H), 2.34 (s,
3H), 7.19 (d, J = 8.4 Hz, 2H), 7.32–7.38 (m, 4H), 7.45–7.50 (m,
1H), 7.88–7.92 (m, 2H); 19F NMR d -149.1 (q, J = 23.1 Hz).
EI-MS (m/z, relative intensity): 242 (M+, 1.6), 137 (87), 105 (100),
77 (30). Anal. Calcd for C16H15FO (FW 242.3): C, 79.32; H, 6.24.
Found: C, 78.94; H, 6.29.
1
´
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0.36 mmol), ketone 4a (54 mg, 0.33 mmol) and aryl halide 2a
(57 mg, 0.36 mmol) was added freshly dried toluene (0.5 mL) and
t-Bu3P (0.0165 mL of 1 M toluene solution, 0.0165 mmol) at 90 ◦C
under nitrogen atmosphere. After 1 hour, the mixture was cooled
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washed with ethyl acetate. The solvent was removed under reduced
´
6 E. Be´langer, C. Houze´, N. Guimond, K. Cantin and J.-F. Paquin, Chem.
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This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 1716–1722 | 1721
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1
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10 Compound 1f is relatively unstable. H NMR d 0.60 (q, J = 7.7 Hz,
6H), 0.92 (t, J = 7.9 Hz, 9H), 2.03 (d, J = 18.1 Hz, 3H), 7.15–7.39
19
(m, 5H). F NMR d -119.6 (q, J = 17.9 Hz). ROSEY showed the
correlation of signal at 2.03 ppm with 0.60 and 0.92 ppm, respectively.
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1722 | Org. Biomol. Chem., 2009, 7, 1716–1722
This journal is
The Royal Society of Chemistry 2009
©